Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis of Danicamtiv in Heart Failure with Reduced Ejection Fraction

Objectives: Danicamtiv is an investigational drug that works as a cardiac myosin activator and could be a potential treatment option for heart failure with reduced ejection fraction (HFrEF). Successful development in this potential indication is contingent on a favorable benefit-risk profile, favorable pharmacokinetic profile and identifying an exposure-response relationship using key echocardiograph (ECHO) parameters indicative of improving systolic function. Population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) modeling were performed to better understand the potential of danicamtiv.Methods: Data from 29 patients in the phase 2a HFrEF PoC study1 was used to perform population PK and PK/PD modeling in NONMEM 7.4. ECHO parameters such as systolic ejection time (SET) and stroke volume were evaluated as PD endpoints using a linear or Emax model. Model performance was evaluated using goodness of fit plots. Final parameter estimates from the population PK-PD model were used to perform simulations using mrgsolve in R to assess dosing. 1000 simulation runs were performed at each evaluated dose. Results: A one compartment model with zero-order absorption described the concentration data well. The inter-individual variability on apparent clearance and apparent volume of distribution was 23.6% and 18.1%. Among ECHO parameters evaluated, SET demonstrated the strongest relationship to danicamtiv exposure, which was described by an Emax model. Heart rate (HR) was a significant, physiologically relevant covariate on baseline SET. Subjects with lower HR had higher SET. Exposure-response relationship with stroke volume data was characterized indirectly through the linear relationship between SET and stroke volume previously described in literature2.Conclusion: Population PK analysis demonstrated relatively low variability and minimal complexities in the PK of danicamtiv. The exposure-response analysis suggests 25-100 mg BID is the optimal clinical dose range to be further evaluated in future studies without the need of therapeutic drug monitoring. Danicamtiv exposure has an indirect relationship with stroke volume through its relationship with SET, which supports the hypothesis that danicamtiv increases contractility. Overall, danicamtiv appears to have favorable properties within the context of other agents with similar mechanism of action in the literature.Citations: 1 Voors AA, et al. Eur J Heart Fail. 2020; 22(9):1649-1658.2Weissler AM, et al. Am Heart J. 1961; 62(3):367-378.